Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor inhuman sporadic adrenocortical tumors: Correlation with genotypic alterations

Several studies have supported the hypothesis that adrenocortical tumor for mation is the result of a multistep process. The angiogenic switch has been proposed to be a key step in tumor progression from adenoma to carcinoma. In this study we measured the cytosolic concentrations of three proteins in volved in angiogenesis [namely platelet-derived endothelial cell growth fac tor vascular endothelial cell growth factor A (VEGF-A), and thrombospondin- 1 (TSP1)] in a series of 43 human sporadic adrenocortical tumors. The tumor s were classified as adenomas (n = 18), transitional tumors (n = 12), or ca rcinomas (n = 13) according to the histological criteria defined by Weiss. Platelet-derived endothelial cell growth factor/thymidine phosphorylase lev els were not significantly different among these three groups. One hundred percent of the adenomas and 73% of the transitional tumors showed VEGF-A co ncentrations under the threshold value of 107 ng/g protein, whereas 75% of the carcinomas had VEGF-A concentrations above this threshold value. Simila rly, 89% of the adenomas showed TSP1 concentrations above the threshold val ue of 57 mug/g protein, whereas only 25% of the carcinomas and 33% of the t ransitional tumor samples did so. Insulin-like growth factor II overexpress ion, a common genetic alteration of adrenocortical carcinomas, was signific antly correlated with higher VEGF-A and lower TSP1 concentrations. The tumo rs from the 6 patients with tumor recurrence after surgical ablation showed significantly higher VEGF-A values than the carcinomas and the transitiona l tumors from patients that did not relapse. Taken together, these data sug gest that a decrease in TSP1 expression is an event that precedes an increa se in VEGF-A expression during adrenocortical tumor progression. The popula tion of premalignant tumors with low TSP1 and normal VEGF-A levels could re present a selective target for antiangiogenic therapies.